Miles David, Papazisis Kostas
ICRF Clinical Oncology Unit, Guy's Hospital, London, UK.
Clin Breast Cancer. 2003 Feb;3 Suppl 4:S134-8. doi: 10.3816/cbc.2003.s.002.
Mucin-1 (MUC-1) is a high-molecular-weight glycoprotein rich in serine and threonine residues that are O-glycosylated. Expression of MUC-1 is increased in breast, ovarian, and other adenocarcinomas, and altered glycosylation results in exposure of novel peptide epitopes and the expression of tumor-associated carbohydrate residues, such as Thomsen-Freidenreich and sialyl-Tn (STn) antigens. Preclinical studies suggested that induction of immune response to tumor-associated carbohydrate moieties results in inhibition of tumor growth. A synthetic STn-keyhole limpet hemocyanin (KLH) vaccine (Theratope) is currently being evaluated in clinical trials as active specific immunotherapy in the treatment of advanced breast cancer. Two phase II trials in 50 breast cancer patients compared the STn-KLH vaccine with and without a single low-dose infusion of cyclophosphamide used as an immunomodulator prior to initiation of treatment. Humoral immune responses were higher in patients who had received low-dose cyclophosphamide intravenously (I.V.) compared with patients who had received no cyclophosphamide or oral cyclophosphamide. There was a statistically significant survival difference between all patients treated with the STn-KLH vaccine (overall median survival, 19.1 months; n = 50) and the retrospective control patients (overall median survival, 9.2 months; n = 104). Furthermore, patients who received cyclophosphamide I.V. prior to the STn-KLH vaccine had median survival rates close to 3 times that of patients in a retrospective, frequency-matched, control group who received conventional therapies (cyclophosphamide-I.V. group, 26.5 months vs. 9.2 months, control group). The trials reported minimal toxicity profile with local reactions in the injection site and some flu-like symptoms. On the basis of the phase II trial results, a phase III clinical trial of the STn-KLH vaccine is underway. The trial was closed to enrollment in March 2001 with the accrual of 1030 women. The final analysis is event driven and is expected to commence mid 2003.
黏蛋白-1（MUC-1）是一种富含丝氨酸和苏氨酸残基的高分子量糖蛋白，这些残基会发生O-糖基化。MUC-1在乳腺癌、卵巢癌和其他腺癌中的表达增加，糖基化改变会导致新的肽表位暴露以及肿瘤相关碳水化合物残基的表达，如Thomsen-Freidenreich和唾液酸化-Tn（STn）抗原。临床前研究表明，诱导针对肿瘤相关碳水化合物部分的免疫反应会导致肿瘤生长受到抑制。一种合成的STn-钥孔戚血蓝蛋白（KLH）疫苗（Theratope）目前正在临床试验中作为活性特异性免疫疗法用于治疗晚期乳腺癌进行评估。两项针对50名乳腺癌患者的II期试验比较了STn-KLH疫苗，一组在治疗开始前联合单次低剂量静脉注射环磷酰胺作为免疫调节剂，另一组未使用。与未接受环磷酰胺或口服环磷酰胺的患者相比，接受静脉注射（I.V.）低剂量环磷酰胺的患者体液免疫反应更高。接受STn-KLH疫苗治疗的所有患者（总体中位生存期为19.1个月；n = 50）与回顾性对照组患者（总体中位生存期为9.2个月；n = 104）之间存在统计学上显著的生存差异。此外，在接种STn-KLH疫苗前接受静脉注射环磷酰胺的患者中位生存率接近接受传统疗法的回顾性、频率匹配对照组患者的3倍（环磷酰胺静脉注射组为26.5个月，对照组为9.2个月）。试验报告的毒性极小，主要是注射部位的局部反应和一些类似流感的症状。基于II期试验结果，STn-KLH疫苗的III期临床试验正在进行。该试验于2001年3月停止招募，共招募了1030名女性。最终分析由事件驱动，预计于2003年年中开始。
